Received: March 23, 2017. Accepted: August 10, 2017. Pre-published: August 17, 2017.
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Correspondence:
wsaber@mcw.edu Ferrata Storti Foundation EUROPEAN HEMATOLOGY ASSOCIATIONHaematologica
2017
Volume 102(11):1823-1832
doi:10.3324/haematol.2017.169581Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/102/11/1823
A
dvances in allogeneic hematopoietic cell transplantation for sickle
cell disease have improved outcomes, but there is limited analysis
of healthcare utilization in this setting. We hypothesized that,
compared to late transplantation, early transplantation (at age <10 years)
Clinical risks and healthcare utilization of
hematopoietic cell transplantation for sickle
cell disease in the USA using merged
databases
Staci D. Arnold,1 Ruta Brazauskas,2,3Naya He,2Yimei Li,4Richard Aplenc,4
Zhezhen Jin,41Matt Hall,5Yoshiko Atsuta,6,7Jignesh Dalal,8Theresa Hahn,9
Nandita Khera,10Carmem Bonfim,11Navneet S. Majhail,12Miguel Angel Diaz,13
Cesar O. Freytes,14William A. Wood,15Bipin N. Savani,16
Rammurti T. Kamble,17Susan Parsons,18Ibrahim Ahmed,8Keith Sullivan,19
Sara Beattie,20Christopher Dandoy,21Reinhold Munker,22Susana Marino,23
Menachem Bitan,24Hisham Abdel-Azim,25Mahmoud Aljurf,26
Richard F. Olsson,27,28Sarita Joshi,29Dave Buchbinder,30Michael J. Eckrich,31
Shahrukh Hashmi,26,32Hillard Lazarus,33David I. Marks,34Amir Steinberg,35
Ayman Saad,36Usama Gergis,37Lakshmanan Krishnamurti,1
Allistair Abraham,38Hemalatha G. Rangarajan,29Mark Walters,39
Joseph Lipscomb,40Wael Saber2,*and Prakash Satwani5,*
*Co-senior Authors
1Emory University Hospital, Atlanta, GA, USA;2CIBMTR (Center for International Blood and
Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; 3Division of Biostatistics, Institute for Health and Society, Medical
College of Wisconsin, Milwaukee, WI, USA; 4University of Pennsylvania, Philadelphia, PA,
USA; 5Division of Pediatric Hematology, Oncology and Stem Cell Transplantation,
Department of Pediatrics, Columbia University Medical Center, New York, NY, USA;
6Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; 7Nagoya
University Graduate School of Medicine, Japan; 8Rainbow Babies & Children’s Hospital,
Cleveland, OH, USA; 9Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY,
USA; 10Department of Hematology/Oncology, Mayo Clinic, Phoenix, AZ, USA; 11Hospital de
Clinicas-Federal University of Parana, Curitiba, Brazil; 12Blood & Marrow Transplant
Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 13Department of
Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain; 14Texas
Transplant Institute, San Antonio, TX, USA; 15Division of Hematology/Oncology,
Department of Medicine, University of North Carolina, Chapel Hill, NC, USA; 16Division of
Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 17Divsion of Hematology and Oncology, Center for Cell and Gene
Therapy, Baylor College of Medicine, Houston, TX, USA; 18Tufts Medical Center, Boston,
MA, USA; 19Duke University Medical Center, Durham, NC, USA; 20University of Ottawa,
Canada; 21Cincinnati Children’s Hospital Medical Center, OH, USA; 22Section of
Hematology/Oncology, Department of Internal Medicine, Louisiana State University Health Shreveport, LA, USA; 23University of Chicago Hospitals, Chicago, IL, USA; 24Department of
Pediatric Hematology/Oncology, Tel-Aviv Sourasky Medical Center, Israel; 25Division of
Hematology, Oncology and Blood & Marrow Transplantation, Children’s Hospital of Los Angeles, University of Southern California Keck School of Medicine, CA, USA;
26Department of Oncology, King Faisal Specialist Hospital Center & Research, Riydah,
Saudi Arabia; 27Division of Therapeutic Immunology, Department of Laboratory Medicine,
Karolinksa Institutet, Stockholm, Sweden; 28Centre for Clinical Research Sormland,
Uppsala University, Sweden; 29Pediatric Hematology, Oncology and BMT, Nationwide
Children’s Hospital and Ohio State University Wexner, Columbus, OH, USA; 30Division of
Pediatrics Hematology, Children’s Hospital of Orange County, Orange, CA, USA; 31Levine
Children’s Hospital, Charlotte, NC, USA; 32Department of Internal Medicine, Mayo Clinic,
Minneapolis, MN, USA; 33Seidman Cancer Center, University Hospitals Case Medical
Center, Cleveland, OH, USA; 34Adult Bone Marrow Transplant, University Hospitals Bristol
NHS Trust, Bristol, United Kingdom; 35Department of Hematology-Oncology, Mount Saini
Hospital, New York, NY, USA; 36Division of Hematology/Oncology, Department of Medicine,
University of Alabama at Birmingham, Birmingham, AL, USA; 37Hematologic Malignancies
& Bone Marrow Transplant, Department of Medical Oncology, New York Presbyterian Hospital/Weill Cornell Medical College, New York, NY, USA; 38Division of Blood and Marrow
Transplantation, Center for Cancer and Blood Disorders, Children’s National Medical Center, Washington, DC, USA; 39Children’s Hospital & Research Center Oakland, Oakland,
NY, USA; 40Health Policy and Management, Rollins School of Public Health, Winship
Cancer Institute, Emory University, Atlanta, GA, USA and 41Department of Biostatistics,
Mailman School of Public Health, Columbia University, New York, NY, USA.
improves outcomes and decreases healthcare utilization. We performed a retrospective study of children
transplanted for sickle cell disease in the USA during 2000-2013 using two large databases. Univariate
and Cox models were used to estimate associations of demographics, sickle cell disease severity, and
transplant-related variables with mortality and chronic graft-versus-host disease, while Wilcoxon,
Kruskal-Wallis, or linear trend tests were applied for the estimates of healthcare utilization. Among 161
patients with a 2-year overall survival rate of 90% (95% confidence interval [CI] 85-95%) mortality was
significantly higher in those who underwent late transplantation versus early (hazard ratio (HR) 21, 95%
CI 2.8-160.8, P=0.003) and unrelated compared to matched sibling donor transplantation (HR 5.9, 95%
CI 1.7-20.2, P=0.005). Chronic graftversus host disease was significantly more frequent among those
translanted late (HR 1.9, 95% CI 1.0-3.5, P=0.034) and those who received an unrelated graft (HR 2.5,
95% CI 1.2-5.4; P=0.017). Merged data for 176 patients showed that the median total adjusted transplant
cost per patient was $467,747 (range: $344,029-$799,219). Healthcare utilization was lower among
recip-ients of matched sibling donor grafts and those with low severity disease compared to those with other
types of donor and disease severity types (P<0.001 and P=0.022, respectively); no association was
demonstrated with late transplantation (P=0.775). Among patients with 2-year pre- and post-transplant
data (n=41), early transplantation was associated with significant reductions in admissions (P<0.001),
length of stay (P<0.001), and cost (P=0.008). Early transplant outcomes need to be studied prospectively
in young children without severe disease and an available matched sibling to provide conclusive
evi-dence for the superiority of this approach. Reduced post-transplant healthcare utilization inpatient care
indicates that transplantation may provide a sustained decrease in healthcare costs over time.
Introduction
Sickle cell disease (SCD) affects approximately 100,000 people in the United States of America (USA) with 2,000 new cases detected via newborn screening annually. There is a lack of clinical predictors to estimate overall outcomes of SCD-associated morbidities, including painful crises and organ dysfunction, which respond vari-ably to medical management, have a devastating impact
on quality of life, and can lead to premature death.1As a
result, many people with SCD are left with sequelae of the disease and its complications. Allogeneic hematopoi-etic cell transplantation (alloHCT) remains the only estab-lished curative option for these individuals.
Despite mounting evidence of rising alloHCT success rates over time, such that the 5-year disease-free survival in children with SCD is now 92%, many still regard alloHCT as an experimental therapy, only for patients
with severe disease.2,3 The indications for alloHCT
remain unclear for non-transplant providers when
com-pared to the benefits of medical management.4In
addi-tion, a recent retrospective study from Belgium suggest-ed that patients with SCD managsuggest-ed msuggest-edically with hydroxyurea may have a better survival than those
treat-ed with alloHCT.5
However, short-term improvements in outcome with medical therapy must be balanced against a disease with an unpredictable clinical course and substantial impact on healthcare utilization. USA individuals with SCD account for an estimated $1.6 billion per year in healthcare costs.6
SCD ranked fifth among the top ten diagnoses of hospital
stays among Medicaid super-utilizers.7 The substantial
healthcare utilization and cost of SCD-related morbidity suggests that a greater focus on curative approaches for this disease is needed.
AlloHCT, when successful, can be curative, but also car-ries the risks of death and substantial morbidity from chronic graft-versus-host disease (GvHD). In addition, the initial cost of alloHCT represents a significant financial
burden of approximately $400,000 in the transplant year.8
This research investigates alloHCT for pediatric SCD using a comprehensive, systematic database analysis
exploring patient-, disease-, and transplant-related vari-ables that may reduce healthcare utilization over time while sustaining excellent clinical outcomes. The findings may provide transplant and non-transplant physicians with additional information to help choose between rec-ommending medical therapy and alloHCT.
Methods
Data sources
Outcomes analysis
The Center for International Blood and Marrow Transplant Research (CIBMTR) database contains alloHCT data for recipients and their donors. Data are collected prior to and at various inter-vals post-alloHCT. Upon CIBMTR registration, a weighted ran-domization scheme selects a subset of patients for more detailed data collection in comprehensive research forms (CRF) which pro-vide more specific transplant-related data (SCD complications, pre-transplant therapy, etc.) (Online Supplementary Figure A1). Healthcare utilization analysis
CIBMTR data on all alloHCT recipients are submitted as trans-plant essential data (TED) (Online Supplementary Figure A2). TED forms record donor and recipient demographic, clinical, and trans-plant data but lack specific CRF data.
The Pediatric Health Information System (PHIS; Children’s Hospital Association, Overland Park, KS, USA) records the corre-sponding inpatient healthcare utilization data. PHIS, a confidential database of 43 member hospitals in the USA (Online Supplementary Figure A3), has participating hospitals submit de-identified data with an encrypted medical record number for identification of readmissions at the same hospital. Institutional and patient-specif-ic information, including patient’s age, date of servpatient-specif-ice, visit codes, length of stay (LOS), adjusted costs, and daily billing data, are col-lected. The PHIS has been merged for similar research purposes including a number of recent scientific publications.9
Merging and validating datasets
Patients in the PHIS database who underwent alloHCT for SCD during the study period were identified utilizing International Classification of Diseases version 9 (ICD9) and alloHCT
diagno-Table 1. Characteristics of USA pediatric patients (age ≤21) receiving first allogeneic hematopoietic cell transplant for sickle cell disease.
Variable Outcomes analysis (CRF) HCU analysis (TED/PHIS)
N (%) N (%)
Number of patients 161 183
Patient-related
Age, median, years 10 (<1-21) 9 (<1-20)
Age at transplant, years <10 86 (53) 100 (55) ≥10 75 (47) 83 (45) Gender Male 81 (50) 101 (55) Female 80 (50) 82 (45) Race African-American 142 (88) 155 (85) Other/missing 19 (22) 28 (15) Karnofsky/Lansky score prior to transplant, % >90 91 (57) 164 (90) ≤90 52 (32) 2 (1) Missing 18 (11) 17 (9) Disease-related
Chronic transfusion Not recorded
No 53 (33)
-Yes 103 (64)
-Missing 5 (3)
-Hydroxyurea Not recorded No 82 (51) Yes 72 (45) Missing 7 (4) -Sickle cell related complications
Stroke 62 (39) 29 (16)
Acute chest syndrome 85 (53) 46 (25)
Recurrent vaso-occlusive pain 89 (55) 134 (73)
Transplant-related
Time from diagnosis to transplant (months) 112 (7-242) 109 (10-227)
Transplant indication Not recorded Stroke 47 (29) Acute chest syndrome 19 (12) Recurrent vasoocclusive pain 35 (22) Excessive transfusion requirements 17 (11) Other*/missing 43 (26) -Conditioning regimen Myeloablative 96 (60) 121 (66) Reduced intensity 54 (33) 58 (32) Non-myeloablative 11(7) 4 (2) Graft source Bone marrow 97 (60) 144 (79) Peripheral blood 9 (6) 4 (2) Cord blood 55 (34) 35 (19) Donor/recipient CMV match -/- 47 (29) 55 (30) -/+ 25 (16) 20 (11) +/- 31 (19) 22 (12) +/+ 41 (25) 51 (28) Missing 17 (11) 35 (19) Donor type Cord blood 55 (34) 35 (19) Related 22 (40) 15 (43) Unrelated 33 (60) 20 (57) HLA identical sibling 67 (42) 126 (69) Well-matched unrelated 27 (17) 10 (5) Other unrelated 11 (7) 7 (4)
sis-related group (DRG) codes (282.6 and 1803, respectively) as well as PHIS procedure codes. These patients were identified within the CIBMTR using a probabilistic algorithm. This process occurred under the guidance of the CIBMTR via the National Marrow Donor Program institutional review board.
TED data were merged with PHIS data to determine risk factors and clinical outcomes associated with healthcare utilization (Online Supplementary Figure A4). A target of 85% merge accuracy was set based on the available database population and previously published reports.9-11 Once linked, the merge accuracy was
assessed by performing institutional level validation under an existing pilot institutional review board process.8This validation
confirmed 100% patient identification in this subset. SCD-related complications identified in the PHIS were validated against CRF data, where available, and showed concordance.
Determination of the severity of sickle cell disease
TED/PHIS variables were used to determine SCD severity. Younger patients (age <10 years) without disease sequelae were considered low risk. Younger patients with disease sequelae or older patients (age ≥10 years) without disease sequelae were con-sidered moderate risk. Older patients with disease sequelae or patients of any age with stroke were considered high risk. Disease sequelae were defined as any episode of acute chest syndrome, and/or three or more vaso-occlusive crises requiring hospitaliza-tion in 1 year.12Variables and outcomes
Outcomes analysis
The study population consisted of children 21 years or younger who had undergone alloHCT for SCD in the USA between 2000-2013 and for whom CRF data were available. The CRF provided information on clinical risk factors and outcomes including overall survival, graft failure, grade II-IV acute GvHD, chronic GvHD, and GvHD-related event free survival (GREFS). GREFS was defined as the survival free of graft failure, chronic GvHD, or death and was used to better assess the post-alloHCT morbidity and associations of clinical risk factors with outcomes.
Healthcare utilization analysis
The total adjusted cost reported to the PHIS is based on a fixed hospital-wide ratio of cost to charge adjusted by geographical location. Adjusted costs for each service unit or department
(clini-cal, pharmacy, imaging, etc.) were reported using service-specific ratios of cost to charge. Charges in the PHIS database were adjust-ed for the wage and price index (publishadjust-ed annually in the Fadjust-ederal Register) and reported from the hospital perspective. Total adjust-ed costs were determinadjust-ed for all inpatient admissions for each patient and include direct medical costs, excluding provider fees, incurred. Indirect costs, outpatient costs, and costs incurred at non-PHIS hospitals were not captured.
Adjusted cost data only were analyzed as the primary outcome of interest because charges and reimbursements vary across each institution and state. Patients without available adjusted cost data were excluded (n=7). Zero-dollar research or study-related costs, reflecting largely workup, medication, or laboratory-related account credits, were included in the analysis. Additional health-care utilization outcomes included number of admissions and LOS. PHIS data were used for descriptive analyses of the selected cohort of patients throughout all the study periods.
Healthcare utilization for the initial alloHCT admission (con-ditioning to first recorded discharge) and alloHCT year (condi-tioning to day +365) was described and considered separately in the analyses. Likewise, the pre-alloHCT period (2 years preced-ing transplant through to the day of transplant conditionpreced-ing) and the post-alloHCT period (2 years from day +366 onward) were analyzed separately (Online Supplementary Figure B).
Analysis of allogeneic hematopoietic cell transplant year Factors influencing healthcare utilization during the alloHCT year were analyzed using the following TED clinical variables -age at transplant, gender, performance status, recipient cytomegalovirus status, income level, insurance, distance from center, SCD complications, donor type, graft source, conditioning regimens, and transplant year. A secondary analysis of disease severity and healthcare utilization was also performed.
Pre- and post-allogeneic hematopoietic cell transplantation com-parison
To standardize costs for comparisons, the total adjusted cost per 30 hospital days was calculated for each patient with both pre- and post-alloHCT inpatient admissions and used as the primary healthcare utilization outcome. The change in an individual patient's healthcare utilization pre- and post-alloHCT was com-pared. This change in healthcare utilization was also analyzed by disease severity. Year of transplant 2000-2006 42 (26) 54 (30) 2007-2013 119 (74) 129 (70) GvHD prophylaxis FK506 ± MMF or MTX 57 (36) 40 (22) CSA ± MMF or MTX 89 (55) 134 (73) Others**/missing 15 (9) 11 (5)
Median follow-up of survivors (range), months 49 (3-138) 49 (11-145)
Well matched- 10/10 HLA match; other unrelated – mismatched or <10/10 HLA match; CRF: comprehensive research form; HCU: healthcare utilization; TED: transplant essential data; PHIS: pediatric health information system; CsA: cyclosporine, FK506: tacrolimus; CMV: cytomegalovirus; CY: cyclophosphamide; ATG: antithymocyte globulin;FLUD-fludara-bine; BU: busulfan; MEL: melphalan; MMF-mycophenolate mofetil; MTX: methotrexate *abnormal transcranial Doppler(TCD)-magnetic resonance imaging angiography with nar-rowing of supraclinoid portions of the internal carotid arteries bilatecally (n=1); abnormal TCD (n=1); acute chest syndrome (ACS); pain; transfusions (n=1); best long-term, life-long option for patient (n=1); both ACS and pain crisis (n=1); cardiomyopathy/pulmonary stenosis (n=1); cerebral vasculopathy (n=1); combination of ACS and pain crisis (chronically ill) (n=1); cranial vasculopathy therefore stroke prevention (n=1); cure sickle cell (n=1); develop allo antibodies, increasing hgb, decreased response to hydroxyurea (n=1); elevated transcranial Doppler (n=1); extensive complications from sickle cell (n=1); family wanted to move back to Nigeria where there is not modern care nor safe trans-fusion(n=1); fever, ileus and mild ACS (n=1); improved quality of life (n=1); increased frequency of pain crisis, at significant risk end organ damage anddysfunction in adulthood (n=1); liver transplant (n=1); matched sibling and hiistory of pain crisis (n=1); osteonecrosis/requiring hip replacement neuropathy-vision loss (n=1); pain;avascular necrosis; magnetic resonance imaging changes to correct SCD (n=1); parents wanted a cure for their child’s SCD (n=1); presence of silent infarcts on magnetic resonance imaging (n=1); rare disease type (n=1); SCD (n=1); **cor+methotrexate (n=1), methotrexate (n=1)
Statistical analysis
Outcomes analysis
After documenting descriptive statistics, Cox propor-tional hazards modeling of CRF level data determined the impact of risk factors on alloHCT outcomes. Due to low event rates and small sample sizes, only bivariate analyses involving one explanatory variable at a time were per-formed. The cumulative incidences of acute GvHD and chronic GvHD were calculated using a competing risk framework.
Healthcare utilization analysis
TED/PHIS data were evaluated to identify whether demographic factors, SCD severity, or alloHCT variables correlate with healthcare utilization changes during the alloHCT year using Wilcoxon, Kruskal-Wallis, or linear trend tests. Healthcare utilization pre- and post-alloHCT was compared using the Wilcoxon signed rank test for continuous variables and the McNemar test for binary variables. Finally, the impact of SCD severity on health-care utilization across these two time periods was exam-ined by Poisson regression for number of visits and LOS. Total adjusted cost were analyzed by linear regression. All analyses were performed using SAS version 9.3 statistical software (Cary, NC, USA).
Results
Outcomes analysis
Demographics
CRF data were available for 161 patients with a median age of 10 years (range <1-21) of whom 50% were female (Table 1; Online Supplementary Table A). The majority (84%) of patients had the HbSS genotype. The most com-monly documented transplant indication was stroke (29%) followed by recurrent vaso-occlusive crises (22%). However, 39% had stroke as a documented SCD
complica-tion, 55% vaso-occlusive crises, and 53% acute chest
syn-drome. The majority of patients reported use of medical therapy, hydroxyurea (45%) and chronic transfusions
(64%). The most common source of a graft for transplan-tation was a matched sibling donor (MSD) (42%) and the majority of patients received myeloablative conditioning (60%).
Transplant outcomes
The 2-year overall survival was 90% [95% confidence interval (CI): 85-95%]: 96% (95% CI: 89-100%) for cord blood transplant (CBT), 94% (95% CI: 86-98%) for MSD transplants, and 74% (95% CI: 54-90%) for transplants from well-matched unrelated donors (MUD) (P=0.002) (Online Supplementary Table B and Online Supplementary
Figure C). All 16 deaths occurred among children with
pre-alloHCT complications of SCD and were due to organ failure (37.5%), infections (25%), GvHD (6.2%), and other/unknown causes (31.2%) (Online Supplementary
Table C). The majority of deaths (62.5%) occurred during
the alloHCT year; six patients died after day +365 (2 from organ failure, 1 from infection, 1 from sickle cell-associat-ed vasculopathy, and 2 from a missing/other unspecificell-associat-ed cause).
The cumulative incidence of acute GvHD at day 100 was 14% (95% CI: 9-20%), and chronic GvHD developed in 31% (95% CI: 23-38%) at 2 years. Of those with chron-ic GvHD, 64% had extensive disease with over half hav-ing a MSD (n=9) or MUD (n=11). The 2-year GREFS was 64% (95% CI: 56-71%).
Bivariate analysis
Age ≥10 years and use of a MUD showed significant negative associations with outcomes (Table 2). The use of cyclosporine-A prophylaxis and year of alloHCT exhibit-ed significant associations with chronic GvHD-relatexhibit-ed outcomes (Table 2).
Healthcare utilization analysis
Demographics
Combined TED/PHIS data were available for 183 patients with a median age of 9 years (range: <1-20) of whom 45% were female (Table 1). With regards to SCD complications, 73% had vaso-occlusive crises, 25% had
Table 2. Cox regression model of outcomes with patient- and transplant- related variables as reported in CRF data (n=161).
Variable Mortality (n=16) Graft failure (n=3) aGVHD (n=33) cGVHD (n=44) GREFS (n=54)
HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)
Age (≥10 years) *21.21 (2.80-160.76) *1.61 (1.17-2.21) *2.63 (1.07-6.45) *1.92 (1.05-3.50) *2.2 (1.26-3.82) Gender (female) 3.09 (1.00-9.57) 1.21 (0.88-1.66) 1.87 (0.78-4.46) 1.49 (0.82-2.73) 1.65 (0.95-2.85) Performance status (<90%) 1.03 (0.34-3.06) 1.11 (0.78-1.58) 1.74 (0.75-4.01) 1.67 (0.91-3.06) 1.57 (0.90-2.74) SCD complications (>2) 1.09 (0.38-3.13) 1.09 (0.78-1.54) 0.79 (0.33-1.91) 1.89 (0.96-3.74) 1.64 (0.90-3.01) Hydroxyurea 2.71 (0.92-7.93) 1.21 (0.89-1.69) 1.72 (0.73-4.03) 1.62 (0.87-3.02) *1.77 (1.00-3.12) Chronic transfusion 1.96 (0.55-6.94) 0.8 (0.57-1.12) 1.13 (0.46-2.76) 1.11 (0.58-2.13) 1.21 (0.66-2.2) CMV+recipient 1.59 (0.56-4.46) 0.92 (0.67-1.26) *2.75 (1.06-7.09) 1.31 (0.72-2.39) 1.37 (0.80-2.36) MUD vs. MSD *5.88 (1.71-20.19) 1.93 (1.22-3.06) *4.36 (1.43-13.34) *2.53 (1.18-5.41) *3.00 (1.51-5.96) CBT vs. MSD 0.92 (0.20-4.1) *0.50 (0.34-0.74) 1.56 (0.47-5.11) 0.94 (0.43-2.05) 1.07 (0.52-2.16) CSA vs. FK506 prophylaxis *0.33 (0.12-0.91) 1.02 (0.72-1.43) 0.68 (0.29-1.6) *0.48 (0.26-0.88) *0.49 (0.28-0.86) AlloHCT after 2006 2.90 (0.66-12.78) 1.11 (0.77-1.58) 3.75 (0.88-16.03) *2.81 (1.18-6.65) *2.25 (1.10-4.61) NMA/RIC vs. MA 1.52 (0.57-4.06) 1.27 (0.92-1.76) 1.17 (0.51-2.71) 1.26 (0.70-2.28) 1.03 (0.60-1.77)
CRF: comprehensive research form; aGvHD: grade 3-4 acute graft-versus-host disease; cGvHD: chronic graft-versus-host disease; GREFS: the survival free of graft failure, chronic graft-versus-host disease, or death; SCD: sickle cell disease; CMV: cytomegalovirus; MUD: matched unrelated donor; MSD: matched sibling donor; CSA: cyclosporina; alloHCT: allo-geneic hematopoietic cell transplant; NMA: non-myeloablative; RIC: reduced intensity conditioning; MA: myeloablative conditioning. *P≤0.05
acute chest syndrome, and 16% had a stroke prior to alloHCT. This translated into 19.7% with low severity disease, 36.6% with moderate severity, and 43.7% with high severity disease (Online Supplementary Table D). The majority of patients received MSD alloHCT (69%) and a myeloablative regimen (66%). Complete cost data were available for 176 of the 183 patients.
Allogeneic hematopoietic cell transplantation admission
The median total adjusted cost per patient was $380,320 [interquartile range (IQR): $297,710-$563,462] with a median LOS of 39.5 days (IQR: 31-53) (Table 3). The high-est costs were associated with room and nursing charges followed by pharmacy costs (Online Supplementary Figure
D).
Allogeneic hematopoietic cell transplantation year
The median total adjusted cost per patient was $467,747 (IQR: $344,029-$799,219) with a median LOS of 52 days (IQR: 38-72) (Table 3). Again, the highest costs were asso-ciated with room and nursing charges followed by phar-macy costs (Online Supplementary Figure D).
During the alloHCT year, age ≥10 years and total
adjust-ed cost per 30 days were not significantly associatadjust-ed (P=0.775) (Table 4). Total adjusted cost was also not asso-ciated with income level, insurance type, or distance from transplant center (P=0.417, 0.918, and 0.253, respectively). The total adjusted cost per 30 days was lower for MSD transplants than for CBT or MUD transplants (P<0.001). CBT was associated with a higher total adjusted cost per 30 days compared to bone marrow transplants (P=0.004). Increased total adjusted cost per 30 days were associated with prior stroke (P=0.004) and vaso-occlusive crises (P=0.009) but not acute chest syndrome (P=0.291). Overall, total adjusted cost per 30 days increased with SCD severity (P=0.022).
Pre- and post-allogeneic hematopoietic cell transplantation
Two-year inpatient healthcare utilization data were available for 134 pre-alloHCT patients and 45 post-alloHCT. The median total adjusted cost per patient was $56,416 (IQR: $32,848-$103,270) pre-alloHCT; this
decreased to $33,112 (IQR: $14,291-$161,959) post-alloHCT (Table 3). The highest adjusted costs during these periods were associated with room and nursing charges followed by laboratory costs (Online
Supplementary Figure D).
Only 41 patients were admitted to the hospital during both pre- and post-transplant periods: healthcare utiliza-tion was significantly reduced with total adjusted cost per 30 days decreasing from $9,393 (IQR: $4,595-$31,291) to $1,873 (IQR: $571-$6,504) (P=0.008) (Figure 1). Of these, 30 patients had high severity disease and had a significant reduction in healthcare utilization (admissions P<0.001, LOS P<0.001, cost P=0.002) (Online Supplementary Table E).
Discussion
Substantial advances in alloHCT for SCD have been made in the past two decades; nevertheless, the eligibility of patients, especially those without severe disease, remains controversial. This study provides additional insight into eligibility as alloHCT outcomes were favor-ably linked to age and donor type suggesting that early alloHCT, before the age of 10 years, and MSD alloHCT have optimal outcomes with the latter also showing a sig-nificant healthcare utilization advantage. These outcomes are in keeping with a recent report from an international study of adult and pediatric MSD recipients describing lower event-free survival rates with increasing age at transplantation and support the recent expert panel rec-ommendation of early alloHCT, prior to the onset of SCD complications, for children with SCD and an available MSD.13,14
MSD alloHCT is not, however, a viable option for many patients, as fewer than 25% will have a suitable HLA-matched donor, necessitating MUD alloHCT for severe disease. Among patients undergoing MUD alloHCT, high-er GvHD risk could be hypothesized as the etiology of poorer outcomes and increased healthcare utilization of older recipients.13,15-17Although the GvHD-related
mortali-ty rate in this study is lower than that in published reports, the low percentage of deaths after day +365 may mitigate
Figure 1. Comparison of 2-year pre- and post-allo-geneic hematopoietic cell transplant inpatient health-care utilization per 30 days as reported in the Pediatric Health Information System (n=41). Pre-alloHCT: the 2 years preceding transplant through to the day of transplant conditioning; Post-alloHCT: day +366 onward; alloHCT: hematopoietic cell transplant; PHIS: Pediatric Health Information System: visits: inpa-tient admissions; LOS: length of stay.
the mortality associated with chronic GvHD. However, the 26% mortality among the MUD alloHCT patients remains well over the 5% mortality threshold accepted by most parents and adolescents for the cure of SCD, as recently published.18 Efforts are still needed to elucidate
more precisely the cause of death (unknown cause in 31%) and transplant-related mortality, especially among patients who died after the alloHCT year, in order to improve transplant procedures to prevent these complica-tions. Our findings support the current practice of
restrict-ing MUD alloHCT to individuals with severe disease.19
The results of the analysis of donor type were consistent with published reports and indicated that the overall sur-vival of patients treated with CBT is similar to that of recipients of MSD bone marrow; however, healthcare
uti-lization was higher with CBT.20Many of the drawbacks of
CBT have been associated with insufficient cell dose. Ongoing research into cord blood expansion may mitigate this limitation and the associated healthcare utilization by
reducing the delay in engraftment.21-23 However, this
cohort of both related and unrelated CBT showed no sta-tistical difference in GREFS or other GvHD outcomes, with a lower cost compared to MUD, suggesting that more analysis is needed to determine the optimal donor type if a MSD is unavailable.
Donor type and SCD severity had a significant impact on both outcomes and healthcare utilization, such that patients with high severity disease and MUD had poorer outcomes and increased healthcare utilization. The corre-lation of healthcare utilization and disease severity, not age, is unclear but may suggest that healthcare utilization is linked to management of persistent SCD complications after alloHCT. Although some end-organ disease is reversible after alloHCT, complications of chronic lung disease and pain can persist in the first year post-alloHCT.24 These complications correlate with increased
healthcare utilization in individuals with SCD.25 In
addi-tion, severe disease remains an indication for MUD alloHCT research trials suggesting this as a possible con-founder in healthcare utilization analysis. MUD outcomes associated with degree of HLA matching, supportive care measures, and infection must also be considered in more detail.16Understanding and mitigating risk factors
associ-ated with poor outcomes and increased healthcare
utiliza-tion following MUD alloHCT is needed because improve-ments in unrelated alloHCT clinical outcomes have the potential to have the greatest clinical and financial impact. The healthcare utilization analysis also described varia-tions over time with a subset of patients having a signifi-cant reduction in healthcare utilization pre- and post-alloHCT. However, the current sample size and/or 2-year time period may not be sufficient to document a change in inpatient healthcare utilization for the entire population of patients. Donor type variations (e.g., CBT) and disease severity within our small sample size likely have a role; more robust analysis is ongoing to understand this phe-nomenon better. In addition, outpatient healthcare uti-lization was not described which may account for the substantial reduction of data available for pre- and post-alloHCT analysis. However, previous publications on healthcare utilization in this population indicated that
out-patient costs remained flat pre- and post-alloHCT.8
Limitations
This is a retrospective study and analysis is therefore limited to variables and data collected by the CIBMTR at the time of alloHCT. This limitation is somewhat mitigat-ed by using multiple sources of data (PHIS and CIBMTR, both TED and CRF forms) to increase sample size and data availability or quality. Retrospective studies also do not allow control of exposures (pre-alloHCT treatment, conditioning, etc.) which may influence outcomes. Bivariate and multivariate analyses can elucidate cofounders; however, due to sample size and low event rates, multivariate analysis was not performed in this study. However, univariate analysis was used to docu-ment the impact of these exposures on outcomes.
The retrospective nature of this database study also does not allow for comparison to controls with SCD who have not been transplanted or incorporation of prospec-tive metrics including quality of life in the analysis. Previous studies have documented the quality of life
improvements gained after alloHCT for SCD.26,27 Other
studies have described significant quality of life differ-ences between non-transplant interventions such as
chronic transfusion and hydroxyurea.1,28 Outcomes and
cost of care for children have been well documented, with a recent analysis of management with hydroxyurea based
Table 3.Inpatient healthcare utilization analysis as reported over time in the PHIS.
Time period Median number Median length Median total
of inpatient admissions of stay per patient adjusted
per patient (IQR) [days (IQR)] cost per patient (IQR)
Pre-alloHCT (n=134) 3 (1-6) 9 (4-18) $56,416 (32,848-103,270) AlloHCT admission - 40 (32-53) $380,320 (n=176) (297,711-563,462) AlloHCT year 2 (1-4) 52 (39-73) $467,747 (n=176) (344,029-799,220) Post-alloHCT 2 (1-4) 8 (3-17) $33,112 (n=45) (14,291-161,960)
PHIS: Pediatric Health Information System; alloHCT: allogeneic hematopoietic cell transplant; Pre-alloHCT - the 2 years preceding transplantation through to the day of transplant conditioning; AlloHCT admission: conditioning to first recorded discharge; AlloHCT year: conditioning to day +365, Post-alloHCT: day +366 onward; IQR: interquartile range.
on Medicaid claims data suggesting that lifetime costs of care may be influenced by the age of hydroxyurea initia-tion.5,29These data largely demonstrate the substantial
life-time costs associated with caring for individuals with SCD and the need to compare costs across the various available treatment options.6Collectively these findings suggest a
multicenter case control study incorporating quality of life is needed to truly understand the full impact of alloHCT on outcomes and healthcare utilization. Prospective stud-ies, including STRIDE2 (NCT02766465), are underway to fill this gap in knowledge of alloHCT for SCD.
The study includes a population that is heterogeneous for donor type, graft source, and conditioning regimen. Analysis of this complex group reflects the current clinical paradigm and its potential to influence healthcare utiliza-tion; however, diversity does introduce confounders. A recent study showed that conditioning regimen does not influence outcomes, and graft source only influences over-all survival, while age and year of transplant influence both overall and event-free survival.13 Survival outcomes
of this cohort are similar to this and other previously pub-lished estimates; these findings suggest that the hetero-geneity of our cohort had limited influence on the out-comes analysis.
The study focuses on a pediatric population which is unique in that children are largely less affected by the dis-ease than their adult counterparts and alloHCT has quite a different long-term impact. Certainly, efforts to offer early MSD alloHCT will have a significant effect on adult care; in the meantime, a large number of adults live with SCD. Therefore, efforts to better understand the cost of “late alloHCT” are needed. Specifically, the combination of favorable outcomes of CBT and advances in cord blood expansion technology may make this a more viable option for adults.21-23Although, this study excluded data on
hap-loidentical transplants, promising clinical outcomes to date suggest this is as another viable means of expanding
the donor pool for adults and children with SCD.24
Ultimately, as the field advances with changes in condi-tioning regimens, modified donor source options, and the advent of gene therapy, ongoing analysis of outcomes and cost will be needed.
Studies of alloHCT for SCD are also limited by the absence of sufficient data on late effects. The risk of impaired fertility and long-term quality of life are not well described. Many studies have documented the impact of alloHCT on sperm production and ovarian failure in this population, but the actual fertility risk remains unclear particularly in light of the use of newer reduced intensity regimens that are less gonadotoxic.3,17,30However, a recent
study of patients’ and parents’ attitudes toward alloHCT
documented that 56% were willing to accept infertility18
suggesting the potential for cure may far outweigh the risk of this complication. At the same time, another recent study of alloHCT not only reported the impact on fertility but also on sexual function and other patient-reported outcomes. In a cohort of individuals studied at least 10 years after transplantation for malignant disease, reports of sexual problems, restrictions in social function, memo-ry and attention concerns, denial of life and health insur-ance were significant.31 Future studies should determine
late outcomes after transplantation for SCD, collecting data not only on end-organ complications but also patient-reported outcomes including organ function and quality of life evaluations for both alloHCT recipients and controls.
Finally, this study involved a USA population and its findings cannot be easily extrapolated to a global popula-tion. However, recent publications have documented the impact of alloHCT throughout the developing world. AlloHCT outcomes in India and Mexico have been described as nearly equivalent to those in the developed world but are performed at substantially lower costs.32,33
International experience suggests that further study of USA transplant approaches to learn potential cost efficien-cies from the global experience will make alloHCT more viable for SCD and other diseases throughout the world.
Table 4. Comparison of inpatient total adjusted costs per 30 days by TED/PHIS patient and transplant variables during the alloHCT year (n=176).
Variables Median Total P Adjusted Cost
(IQR, $ per 30 days) Patient-related Age 0.775 <10 years 121,506 (89,377-180,961) ≥10 years 128,731 (90,120-167,746) Gender 0.263 Male 119,492 (83,738-172,825) Female 132,841 (93,741-172,900) Performance status 0.529 <80% 106,761 (93,741-119,781) ≥80% 126,343 (90,086-171,574) CMV+recipient 0.061 Yes 132,768 (104,432-190,135) No 122,517 (83,541-156,185) History of stroke <0.001 Yes 167,746 (102,818-233,031) No 121,506 (87,291-157,945) History of VOC 0.009 Yes 135,464 (93,552-187,355) No 111,261 (83,928-142,718) History of ACS 0.291 Yes 132,841 (93,552-186,437) No 123,088 (84,321-171,574) SCD severity 0.022 High 130,380 (93,552-201,784) Low 112,565 (90,052-144,859) Transplant-related Donor type <0.001 Matched sibling 112,835 (85,640-145,895) Well-matched unrelated 246,903 (151,522-279,149) Cord blood 170,322 (102,034-217,186) Graft source 0.004 Cord blood 170,322 (102,034-217,186) Bone marrow 120,331 (88,195-153,998) Conditioning 0.953 Non-myeloablative 119,754 (75,011-210,103) RIC (N=1) 53,319 Myeloablative 126,993 (93,746-160,187) AlloHCT year 0.001 Before 2006 97,416 (69,488-131,898) After 2006 135,464 (102,818-190,135)
TED: transplant essential data; PHIS: Pediatric Health Information System; alloHCT: allogeneic hematopoietic cell transplant; IQR: interquartile range; VOC: vaso-occlusive crises; ACS: acute chest syndrome; RIC: reduced intensity conditioning.
Conclusion
Performing analyses of both clinical and financial out-comes is challenging because of the lack of a single, exhaustive data source. The data merging process is invaluable in that it successfully utilizes existing datasets and combines them to create the largest and most accurate surrogate for assessment in a comprehensive manner. This provides proof of principle for this methodology and type of analysis and builds a foundation for future research in the field. Specifically, the superior clinical outcomes among children <10 years old lay the basis for prospective studies among low-risk SCD patients for whom a MSD is available. In addition, alloHCT, although costly, can pro-vide a sustained decrease in healthcare utilization for patients over time. These results and future studies will provide guidance and insight into health policy determina-tions for the optimal use of this curative therapy for chil-dren with SCD.
Acknowledgments
Special acknowledgments to our patients and families. The numerous mentors and advisors who helped develop and support this project. Dr. Arnold was supported in part by a Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program award. Dr. Aplenc was supported by 1R01CA166581. CIBMTR Support List: the CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health
Resources and Services Administration (HRSA/DHHS); two Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; Alexion; *Amgen, Inc.; Anonymous dona-tion to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc.; Be the Match Foundation; *Bluebird Bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cellular Dynamics International, Inc.; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children’s Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; *Sanofi US; *Seattle Genetics; *Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government. *Corporate Members.
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